Brain Phospholipid Metabolism, In Relation To Function

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In vivo metabolism (1) Rats deprived of nutritionally essential n-3 (omega-3) polyunsaturated fatty acids (PUFAs) for 3 generations had deficits in learning and memory. Their brain phospholipids showed a reduced concentration of n-3 docosahexaenoic acid, no change in the concentration of n-6 arachidonic acid, and an increased concentration of n-6 docosapentaenoic acid. The turnover rate of docosahexaenoate in brain phospholipids was markedly reduced but nevertheless active, whereas the turnover rate of arachidonic acid was unchanged. Brain function and structure depend on competition between docosahexaenoic and arachidonic acids. The turnover rates appear to be independently regulated by specific sets of enzymes. (2) In rats, 3-5% of brain arachidonic acid and 2-8% of brain docosahexaenoic acid are replaced daily by the respective unesterified PUFAs from plasma. In humans, the arachidonate replacement rate is 0.3% per day. Based on measured brain PUFA concentrations, these rates give half-lives of 1-2 weeks in rats and 10 weeks in humans for brain PUFA replacement from plasma. PUFA replacement in disease states can be enhanced by dietary supplementation. (3) Radiolabeled arachidonic acid can be used to image and quantify phospholipid metabolism in heart as well as in brain. When injected intravenously in unanesthetized rats, it is selectively incorporated into membrane phospholipids in the heart. In vivo Imaging (1) Clinical protocols were initiated to use PET to image incorporation of arachidonic and docosahexaenoic acids into the human brain. Chronic alcoholism, bipolar disorder and Parkinson disease can be studied with this method. (2) Our fatty acid method suggests that brain dopaminergic signaling is hyperactive in Parkinson disease, accounting for abnormal motor movements. In a rat model of Parkinson disease (chronic unilateral lesion of substantia nigra), uptake of intravenously injected radioactive arachidonic acid into basal ganglia-frontal cortex circuitry was increased ipsilateral to the lesion, in response to a dopaminergic D2 receptor agonist. This receptor is coupled to phospholipase A2 activation and the release of arachidonic acid for signal transduction. (3) Chronic administration to rats of the dopaminergic D2 antagonist, haloperidol, decreased radiolabeled arachidonic incorporation from plasma into basal ganglia-frontal cortex circuits. Haloperidol's antipsychotic effect may be due to downregulation of D2-receptor mediated arachidonate signaling in these circuits. (4) Myoinositol, which is elevated in the DS brain, also is elevated in the brain of the Ts65Dn mouse model for DS. This model thus can be used to study the effect of myoinositol elevation on signaling and the phosphatidylinositol cycle.